DESCRIPTION: Dr. Jirtle's group has recently demonstrated that the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2r) gene is an important tumor suppressor in human and rat hepatocellular carcinoma (HCC). The proposed studies will focus on mouse model systems. In Aim 1, HCCs from two carcinogen models will be analyzed to demonstrate that M6P/IGF2r gene lesions are present. Aim 2 studies will evaluate the effect of M6P/IGF2r gene replacement in an HCC line that lacks a functional gene. In Aim 3, a M6P/IGF2r transgenic that overexposes the gene will be evaluated for its sensitivity to liver carcinogenesis by two agents, diethylnitrosamine (DEN) and di[2-ethyl-hexyl]phthalate (DEHP). Finally, for Aim 4 studies, a transgenic mouse will be constructed with inducible knock-out of the M6P/IGF2r gene for evaluation in the carcinogenesis models.